Injectable, Biodegradable Bone Cements and Methods of Making and Using Same

ABSTRACT

Compositions of, methods of making, and methods of using alkaline earth phosphate bone cements are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. patent application Ser. No.14/375,927, filed under 35 U.S.C. §371 on Jul. 31, 2014, published;which is the national stage entry of international applicationPCT/US13/24040, filed under the authority of the Patent Cooperationtreaty on Jan. 31, 2013, published; which claims the benefit of U.S.Provisional Patent Applications Nos. 61/593,094 and 61/697,059, filedunder 35 U.S.C. §111(b) on Jan. 31, 2012 and Sep. 5, 2012, respectively.The entire disclosures of all the aforementioned applications areincorporated herein by reference for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with no U.S. Government support and the U.S.Government has no rights in this invention.

FIELD OF THE INVENTION

This invention generally relates to bone cement compositions and methodsof making, strengthening, and using bone cement compositions.

BACKGROUND OF THE INVENTION

There is no admission that the background art disclosed in this sectionlegally constitutes prior art.

Conditions related to back pain account for more hospitalizations thanany other musculoskeletal condition. The back is the body part mostoften involved in work-related disabilities. Back pain is the mostprevalent medical disorder in industrialized societies. More than 75% ofthe United States population will be affected by low back pain over thecourse of their lifetime. According to the statistics from the NationalInstitutes of Health, back pain is the second most common medicalcondition for which people seek treatment, accounting for more than 50million physician office visits annually. Low back pain is the leadingcause of disability in people younger than age 50.

In order to alleviate back pain, many people undergo surgicalintervention Implanted instrumentation is used in many types of spinalsurgeries to help join vertebrae together and restore stability.Additionally, implants such as plates, rods, and screws help correctdeformity and bridge spaces created by the removal of damaged spinalelements. Bone cement is desired in clinical situations to enable properfixation of the implants. Bone cement is also used in a wide variety ofother medical and dental applications, such as in the repair ofcranio-maxillofacial defects, tooth fillings, or spinal fusions.

The bone cements commonly used are poly methyl methacrylate (PMMA)cements. Bone cements made from PMMA have several disadvantages. Namely,methacrylates and methacrylic acid are known irritants to living tissue.PMMA-based cements can generate free radicals in vivo, which can damagesurrounding tissue. PMMA-based cements are also not biodegradable, andthe polymerization reaction involving PMMA is highly exothermic,possibly causing damage to surrounding tissue when cured.

Another problem with many conventional bone cement formulations is thenecessity of mixing and storing two or more solid powder ingredients,which reduces their batch-to-batch reproducibility and shelf life.Homogeneous mixing of two solids is not an easy task. Optimal cementsshould be able to set in a liquid medium during the normal setting timewithout being washed away. This is important for injectability andcohesiveness. Both of these issues can be enhanced by incorporating apolymer in the setting solution. However, cement compositions containingpolymers with two solid ingredients still have poor injectabilitybecause homogeneous mixing of two solid ingredients is not easy.

Some possible alternatives to PMMA-based cements are cements made fromvarious alkaline earth phosphates. These include calcium phosphatecements, magnesium phosphate cements, and strontium phosphate cements.Of all alkaline earth phosphates, Ca—P cements, or CPCs, are the mostcommon CPCs are based on different compounds within the CaO—P₂O₅ (Ca—P)binary system. These compounds include Ca-hydroxyapatite,Ca₁₀(PO₄)₆(OH)₂ or simply hydroxyapatite, which is most well known dueto its similarity to natural bone mineral. Other compounds in the Ca—Pbinary system include tetracalcium phosphate (TTCP, Ca₄(PO₄)₂O),tricalcium phosphate [α-TCP, α-Ca₂(PO₄)₂ and β-TCP, β-Ca₃(PO₄)₂],dicalcium phosphate anhydrous (DCPA, monetite, CaHPO₄), di-calciumphosphate dehydrate (DCPD, brushite, CaHPO₄.2H₂O), and octacalciumphosphate (OCP, Ca₈H₂(PO₄)₆.5H₂O). CPCs offer several advantages overPMMA-based cements, such as greater malleability, allowing the cement tobetter adapt to a defect's site and shape. CPCs also offer betterbiocompatibility, bioactivity, osteoconductivity, and bioresorbability.

Mg—P cements (MPCs) in the market are mainly based on the composition ofMgNH₄PO₄, formed via reaction between acid part (ammonia salts) and basepart (MgO or Mg(OH)₂), resulting in exothermic phenomena. However, therelease of ammonia during setting and degradation of MPCs compromisesthe biocompatibility of the cements. Sr—P cements (SPCs) are Ca—P orMg—P cements doped with strontium. Strontium can promote cell growth andprovides radio opacity.

It would be desirable to formulate bone cement compositions that areeasily made and possess improved strength, mechanical properties, andbioactivity. It would be further desirable if the properties of suchbone cements allow them to be readily used in the surgical theater.

SUMMARY OF THE INVENTION

In a first aspect, there is provided herein a bone cement compositionmade from mixing one powder component, a setting solution, and abiocompatible polymer. The powder component comprises a basic source ofcalcium, magnesium, or strontium. The setting solution comprisesphosphoric acid. A biocompatible polymer is incorporated into thesetting solution prior to mixing with the powder. In certainembodiments, the biocompatible polymer is chitosan and issurface-phosphorylated then incorporated into the setting solution at aconcentration ranging from about 0% to about 10% by weight of thesetting solution. Upon mixing, a paste forms that either (a) hardensinto a solid mass some period of time after mixing the powder with thesetting solution, or (b) is irradiated with electromagnetic radiation toform dry powders that are then mixed with a second setting solution toform a bone cement paste that sets into a hardened mass. In certainembodiments, the cement has a setting time of from about 30 minutes toabout 60 minutes.

In a second aspect, there is provided herein a method of reducing theexothermicity of bone cement compositions. The method involvesirradiating a bone cement paste (made from acid-base reactions) withelectromagnetic radiation to form dry powders, then mixing the drypowders with a setting solution comprising water, saline, or nanosilicasol to form a bone cement paste that sets into a hardened mass. Thereaction does not change the pH and does not release any heat. Themethod described herein also produces strengthened bone cementcompositions suitable for weight-bearing applications.

Further disclosed herein are methods of making bone cement. One methodcomprises mixing a single powder component with a setting solution and abiopolymer to form a paste, and allowing the paste to set into ahardened mass. Another method comprises forming a bone cement paste froman acid-base reaction, irradiating the bone cement paste withelectromagnetic radiation to form dry powders, and mixing the drypowders with a setting solution comprising water, saline, or nanosilicasol to form a radiation-assisted bone cement paste that sets into ahardened mass after a period of time.

Further disclosed herein is a method of producing a settable CPC/MPC/SPCwith minimum exothermic properties. Further disclosed are methods ofusing a bone cement to treat a subject, to deliver a drug, to increasethe biocompatibility of titanium implants, to increase the strength of acalcium sulfate dehydrate cement, to fill a tooth defect, to fill a holeor cavity in a bone, and to replace or treat weakened or collapsedvertebrae.

Further disclosed are various kits for making a bone cement compositionas described herein.

Various aspects of the invention will become apparent to those skilledin the art from the following detailed description of the preferredembodiments, when read in light of the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The following drawings may contain hidden features or elements shown indotted lines and may include phantom views of various components orelements shown in dashed-dotted lines.

FIG. 1 is a comparison of XRD patterns for monetite cement pastes formedbetween ten minutes and twelve hours of setting.

FIG. 2 illustrates the rheological properties of cements with varyingamounts of chitosan.

FIG. 3 is a series of SEM images of morphological structures forchitosan monetite composites with various content of chitosan by weight:0% (A), 5% (B), 10% (C), and 20% (D).

FIG. 4 is an SEM image illustrating the in vitro response ofchitosan-containing cements.

FIG. 5 is a graph showing a comparison of the compressive strength ofmonetite cement, monetite cement with commercially available chitosan,and monetite cement with surface-phosphorylated chitosan.

FIG. 6 shows SEM images of (a) monetite precursors formed aftermicrowave treatment; (b) monetite cement formed by direct mixing withCa(OH)₂ and H₃PO₄; and (c) hardened monetite cement after microwavetreatment.

FIG. 7 is a graph showing the injectability properties of cements basedon the percent of chitosan present in the cement.

FIG. 8 is a comparison of XRD patterns of a monetite cement formed usinga regular acid-base reaction, and a monetite cement formed using themicrowave-assisted approach disclosed herein.

FIG. 9 is an SEM image of preosteoblast cells on monetite-silica cementsamples 72 hours after seeding. The biocompatibility of the surface isshown by cell spreading. Cement particles are visible underneath theosteoblasts. This shows the biocompatibility of the cement.

FIG. 10 shows compressive strength values of monetite-silica, monetite,monetite (old), Chem-ostetic, and calcibon cements. Microwave treatmentcan improve the compressive strength of monetite cement, comparable tonon-load bearing cements on the market such as Chem-Ostetic. Theaddition of nanosilica sol to monetite significantly improves itsstrength, making the load-bearing of monetite-silica cement much higherthan Calcibon, a commercial weight-bearing CPC on the market.

FIG. 11 is a graph showing compressive strength values ofmonetite-silica proceeding with time.

FIG. 12 is a graph of temperature over time, showing the difference inheat generated during mixing of monetite cement made with and withoutthe microwave-assisted technique. As seen from this graph, themicrowave-assisted technique generates significantly less heat.

FIG. 13 displays XRD patterns of Mg—P precursors formed after microwavetreatment, Mg—P cement formed by direct mixing with Mg(OH)₂ and H₃PO₄,and hardened Mg—P cement after microwave treatment.

FIG. 14 shows SEM images of (a) Mg—P precursors formed after microwavetreatment; (b) Mg—P cement formed by direct mixing with Mg(OH)₂ andH₃PO₄; and (c) hardened Mg—P cement after microwave treatment.

FIG. 15 is an SEM image of the Mg—P cement after 7 days incubation insimulated body fluid. The Mg—P cement converted into apatite withplate-like crystals and Mg²⁺, Ca²⁺, Na⁺, and PO₄ ³⁻ ions.

FIG. 16 is an XRD pattern of the Mg—P cement after 7 days incubation insimulated body fluid. The pattern indicates partial newberyite(MgHPO₄.3H₂O) was converted into bobierrite (Mg₃(PO₄)₂.8H₂O).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Throughout the entire specification, including the claims, the word“comprise” and various of the word, such as “comprising” and “comprises”as well as “have,” “having,” “includes,” and “including,” and variationsthereof, means that the named steps, elements, or materials to which itrefers are essential, but other steps, elements, or materials may beadded and still form a construct within the scope of the claim ordisclosure. When recited in describing the invention and in a claim, itmeans that the invention and what is claimed is considered to be whatfollows and potentially more. These terms, particularly when applied toclaims, are inclusive or open-ended and do not exclude additional,unrecited elements or method steps.

Various embodiments are described herein in the context of composition,and method, formula, system, and/or process for preparing, bone cementshaving improved mechanical properties. Those of ordinary skill in theart will realize that the following detailed description of theembodiments is illustrative only and not intended to be in any waylimiting. Other embodiments will readily suggest themselves to suchskilled persons having the benefit of this disclosure. Reference to an“embodiment,” “aspect,” or “example” herein indicate that theembodiments of the invention so described may include a particularfeature, structure, or characteristic, but not every embodimentnecessarily includes the particular feature, structure, orcharacteristic. Further, repeated use of the phrase “in one embodiment”does not necessarily refer to the same embodiment, although it may.

In the interest of clarity, not all of the routine features of theimplementations or processes described herein are shown and described.It will, of course, be appreciated that in the development of any suchactual implementation, numerous implementation-specific decisions willbe made in order to achieve the developer's specific goals, such ascompliance with application- and business-related constraints, and thatthese specific goals will vary from one implementation to another andfrom one developer to another. Moreover, it will be appreciated thatsuch a development effort might be complex and time-consuming, but wouldnevertheless be a routine undertaking for those of ordinary skill in theart having the benefit of this disclosure.

A state-of-the-art bone cement composition should meet the followingcriteria: (1) the composition should use one solid component, thusenabling easy mixing; (2) the composition should use solids that do notneed high-temperature processing; (3) the composition should use asetting solution of an aqueous nature; (4) the hardening (setting)process should not be exothermic so that no tissue necrosis takes place;(5) the final phosphate phase should be biodegradable, for example MgP,SrP, TCP, DCPA, or DCPD, thus enabling regeneration of bone tissues; (6)the composition should be injectable (i.e., of the correct rheologicalproperty) to fill a bone defect; (7) the composition should harden in asuitable timeframe to give a surgeon an optimum window of opportunity toinject the cement before hardening takes place; (8) the cement shoulddevelop strength of the trabecular bone within a window of ten minutesto two hours for the weight bearing of the patient and ultimatelydeveloping even higher strength within 24 hours after the operation; (9)the cement should be radio-opaque for quick identification by X-rays;(10) the cement should be biocompatible and biodegradable, as determinedby in vitro testing; and (11) the cement should maintain the abovecharacteristics in vivo as well.

In accordance with the above, provided herein is a bone cementcomposition made from a single powder component comprising a basicsource of calcium, magnesium, or strontium, and a setting solutioncomprising H₃PO₄. In certain embodiments, the powder comprises Ca(OH)₂or Mg(OH)₂, and the setting solution further comprises a biocompatiblepolymer, deionized water, a buffer such as NaHCO₃, and citric acidmonohydrate. In particular embodiments wherein the powder is Ca(OH)₂,the resulting bone cement is a dicalcium phosphate anhydrous (CaHPO₄,also known as monetite or DCPA) cement that dispenses with severalproblems in conventional bone cement formulations. The CPCs currentlyavailable commercially are either apatite CPCs (such as α-BSM®,BoneSource®, Calcibon®, and Biopex®) or brushite CPCs (such as ChronOSInject®, Eurobone®, and VitalOS®). However, monetite is a goodalternative to apatite and DCPD cements because it has similar chemicalcomposition and solubility to DCPD, it exhibits desirable propertiesthat support bone regeneration, and it does not reprecipitate intoapatite in vivo.

The monetite bone cement disclosed herein is based on an acid-basereaction between H₃PO₄ and Ca(OH)₂, with NaHCO₃ as a pH buffer. Themonetite cement is made from a single powder component and a settingsolution. The powder comprises Ca(OH)₂, which is readily availablecommercially and relatively inexpensive. The Ca(OH)₂ powder can be usedwithout any further treatments or additives, and is not subjected tohigh temperatures during synthesis. The setting solution comprisesphosphoric acid (H₃PO₄). In certain embodiments, a biocompatible polymeris incorporated into the setting solution to provide cohesiveness to thecomposition. The biopolymer further enhances the mechanical propertiesof the cement by providing a toughening mechanism against thepropagation of a crack.

In certain embodiments, the biocompatible polymer comprises chitosan[(1-4)-2-amino-2-deoxy-β-D-glucan] and is present from about 0% to about20% by weight of the total composition. More particularly, the chitosanis present from about 1% to about 5% by weight of the total composition.Chitosan is a compound found primarily in the exoskeletons of arthropodsand has several desirable attributes for incorporation into cementcompositions. It has a polycationic carbohydrate structure similar tothat of hyaluronic acid, an extracellular matrix molecule. Chitosan'scationic nature provides a suitable substrate for cell adhesion andprevention of washout in a cavity. Chitosan is both biocompatible andbioactive (e.g., osteoinductive), as well as haemostatic. While liquidat room temperature, chitosan tends to gel at higher temperature such asthe physiological temperature of 37° C. These properties contribute tothe cement composition's injectability, bioactivity, cohesiveness, andimproved mechanical properties.

In certain embodiments, the chitosan is surface-phosphorylated prior tobeing incorporated into the setting solution. One method of achievingthis surface modification is by dissolving chitosan in orthophosphoricacid, urea, and N,N-dimethyl formamide, heating and stirring themixture, then pouring the mixture into water and filtering it to collectsurface-phosphorylated chitosan particles. Phosphorylation improves theadhesion of the chitosan to the cement.

The setting solution comprises H₃PO₄ but may further comprise deionizedwater and a suitable buffer, such as sodium bicarbonate (NaHCO₃)dissolved in water, to increase the pH of the setting solution, as wellas citric acid monohydrate (CAM) to improve the handling of the finalpaste. In some embodiments, the powder component is mixed with deionizedwater to form a basic solution which is then mixed with the settingsolution, while in other embodiments the powder component is mixeddirectly with the setting solution. In one embodiment, the powder andsetting solution are mixed in a powder-to-liquid ratio of about 1 g per0.4 mL. In another embodiment, the powder-to-liquid ratio is about 1 gper 0.6 mL. Many other ratios are possible. The powder-to-liquid ratiois easily changed by using different amounts of deionized water in thesetting solution.

Upon mixing with the setting solution, a paste is formed by redoxreactions between the H₃PO₄ and the Ca(OH)₂. The paste is a monetite(DCPA) cement that sets into a hardened mass between 30 and 60 minutesafter mixing. The hardened monetite cement is stable in deionized waterat 37° C. due to a thin apatitic film on its surface, but converts toapatite readily in carbonated solutions at a slightly elevatedtemperature of 95-100° C. The monetite cement has a higher solubility atneutral pH in physiological solutions than other CPCs and stimulatesapatite formation in simulated body fluids after a relatively shorttime. Increased pH values also lead to hydrolysis of monetite to formapatite.

Currently available CPCs are based on a powder component comprising atleast two or more CaP or Ca— or P-containing phases. The components ofthese powder mixtures may undergo solid state reactions that limit theirshelf life and storage conditions. The requirement of only one powdercomponent for the monetite cement disclosed herein is thus advantageous.The monetite cement also exhibits a higher in vivo resorbability incomparison to apatitic cements. Furthermore, unlike α-TCP and TTCPpowders, the monetite cement powders can be synthesized at roomtemperature, alleviating the need to quench the cement phases to ambienttemperatures which may require delicate grinding and cause contaminationor undesired hydrolysis during grinding.

In addition to a variety of surgical applications discussed below, themonetite bone cement disclosed herein can be used as a coating ontitanium implants that converts to apatite, making this a usefultechnique for increasing the biocompatibility of titanium implants.Also, the monetite bone cement can be added to calcium sulfate dehydrate(CSD) cements to significantly increase the mechanical properties of theCSD cements.

Further disclosed herein is a method of reducing the exothermicity ofalkaline earth phosphate bone cements such as the monetite cementdescribed above, and a series of alkaline earth phosphate bone cementswith significantly reduced exothermicity. The method can be utilizedwith any cement paste formed from an acid-base reaction and producesalkaline earth cements with minimum exothermicity capable of use inweight-bearing applications. The process involves subjecting a cementpaste comprising reactants of powder and liquid in an optimal ratio(before the paste sets) to electromagnetic radiation with frequenciesbetween about 10⁶ Hz to about 10²² Hz, such as microwaves, to producedried CPC/MPC/SPC powders. The irradiation preserves the cement in itsinitial reaction stage and causes the paste to form a brittle mass. Theirradiation also removes water to stop the hydrolysis andcrystallization of CPC/MPC/SPC precursors, and renders all CPC/MPC/SPCprecursors inactive. The brittle mass is crushed into fine powders. Thefine powders are then mixed with a setting solution comprising water,saline, or nanosilica sol. Upon contact with the setting solution,hardening of the paste continues and the cement strength increases. Fromthis process, a viscous and moldable paste is obtained with minimumexothermicity. The paste sets to a firm mass after a period of time.

The cements produced using this electromagnetic radiation-assistedtechnique have improved hardening and mechanical properties withsignificantly minimized exothermicity and no change in pH. Whennanosilica sol is used as the setting solution, further improvement tothe mechanical properties of the cements compared to water or otheraqueous solution is achieved. This is due to the nanosilica solproviding amorphous calcium silicate hydrate (CSH) gel for initialstrength reinforcement and increased bioactivity. As time proceeds, theCSH gel polymerizes and hardens to provide a solid network to supportthe cement, thereby providing more strength and promoting bioactivity ofthe cement. It should be noted that the addition of nanosilica, or anyother additive, can alter the desired powder-to-liquid ratio needed toproduce the final cement.

Some Si-containing CPCs/MPCs/SPCs are already available commerciallywith adequate osteoconducitivty. However, commercially availableSi-containing cements are referred to as silicon or silicate“substituted” cements. “Substitution” in this context means Si entersinto the relevant CPC/MPC/SPC lattice (crystal structure), thusmodifying osteoconductivity and osteoinduction. Such cements aretypically not suitable for orthopedic applications because they aredifficult to synthesize, have a long setting time, show poor mechanicalstrength for load-bearing applications, and may require high-temperaturemelting. (See Gibson I R, Best S M, Bonfield W., ChemicalCharacterization of Silicon-Substituted Hydroxyapatite, J Biomed MaterRes 1999; 44:422-428.) In the CPC—SiO₂, MPC-SiO₂, and SPC—SiO₂compositions presently disclosed, Si does not modify the lattice in anyway. Rather, as disclosed herein, Si provides a strong bond between thecement particulates without deteriorating the osteoinduction orosteoconductivity. The resulting composition shows enhancedbiocompatibility, bioactivity, and mechanical performance compared toconventional CPCs/MPCs/SPCs. The osteoinduction and osteoconductivityare mainly provided by the specific phosphate phase formed. In certainembodiments, the cement is monetite (DCPA), but the same mechanismapplies to MPCs or SPCs.

The cements disclosed herein are useful for repairing a wide variety oforthopedic conditions. By way of non-limiting example, the cements maybe injected into the vertebral body for treatment of spinal fractures,injected into long bone or flat bone fractures to augment the fracturerepair or to stabilize the fractured fragments, or injected into intactosteoporotic bones to improve strength. The cements are useful in theaugmentation of a bone-screw or bone-implant interface. The cements mayalso be formed into bone-filling granules to replace demineralized bonematrix materials. The cements disclosed herein provide an elasticmodulus nearer to that of bone than conventional bone cements whilebeing biodegradable—allowing the cement to be replaced by natural bonebut at the same time mimicking the properties of normal bone and beingable to sustain weight-bearing. Because of their enhanced weight-bearingcapacity, the cements disclosed herein can provide scaffold support forvarious types of vertebral fracture and could be used in tibia plateaureconstruction, wrist fracture reconstruction, calcaneal reconstruction,and prophylaxis strengthening of the hip bone. Further, because of theirenhanced biocompatibility and bioactivity, the cements disclosed hereinmay be used as delivery vehicles for drugs, genes, proteins, cells,DNAs, or other molecules.

Additionally, the cements are useful as bone filler in areas of theskeleton where bone may be deficient. In this context, the cements areintended to fill, augment, and/or reconstruct maxillofacial osseous bonedefects, including periodontal, oral, and cranio-maxillofacialapplications. The cements are packed gently into bony voids or gaps ofthe skeletal system (i.e., extremities, pelvis, and spine), includinguse in postero-lateral spinal fusion or vertebral augmentationprocedures with appropriate stabilizing hardware. The cements may beused to fill defects which may be surgically created osseous defects orosseous defects created from traumatic injury to the bone. In certainembodiments, the cements provide a bone void filler that resorbs and isreplaced by bone during the healing process.

Injectability and cohesiveness are clinically important issues relatedto the use of any bone cement. When the repair of a large defect isunderway, a successful bone cement composition should flow smoothly andhomogeneously, resulting in eventual uniform resorption. Embodiments ofthe bone cement formed from the radiation-assisted technique wherein thesetting solution comprises nanosilica gel have improved injectabilityand cohesiveness. The exothermic properties of a bone cement are alsoclinically important. Because the silica-monetite cement disclosedherein gives off little heat, the silica-monetite cement does not causenecrosis of surrounding tissue and could be used as a drug deliverydevice. Due to the cement's increase in strength from the nanosilicabonding, the silica-containing cements described herein can be used forweight-bearing applications. Examples of weight-bearing applicationsinclude use in osteoporotic vertebral compression fractures in the spineand other traumatic fractures like tibia plateau fractures.

Various additives may be included in any of the compositions describedherein to adjust their properties and the properties of the hardenedcements produced. Examples of suitable additives include proteins,osteoinductive and/or osteoconductive materials, X-ray opacifying agentssuch as strontium phosphate or strontium oxide, medicaments, supportingor strengthening filler materials, crystal growth adjusters, viscositymodifiers, pore-forming agents, antibiotics, antiseptics, growthfactors, chemotherapeutic agents, bone resorption inhibitors, colorchange agents, immersing liquids, carboxylates, carboxylic acids,α-hydroxyl acids, metallic ions, or mixtures thereof. Other suitableadditives include substances that adjust setting times (such aspyrophosphates or sulfates), increase injectability or cohesion (such ashydrophobic polymers like collagen), alter swelling time, or introducemacroporosity (such as porogens).

If a reduced particle size of a particular cement composition disclosedherein is desired for a certain application, such particle reduction canbe accomplished by using, for example, an agate pestle and mortar, aball mill, a roller mill, a centrifugal-impact mill and sieve, a cuttermill, an attrition mill, a chaser mill, a fluid-energy mill, and/or acentrifugal-impact pulverizer. Particle size reduction may be desiredfor treating bone defects through a method that involves breaking up thehardened bone cement into pellets and filling a hole or cavity in thebone with the pellets.

The cements disclosed herein may be supplied to the user in a variety offorms, including as powders or as a powder mixture which is later mixedwith a solvent to make slurry or putty, or as a pre-mixed putty whichmay a contain nonaqueous extender, e.g., glycerine and/or propyleneglycol. The pre-mixed putty would allow the cement to set upon contactwith water. Also, any of the cements disclosed herein can be deliveredvia injections. That is, a cement paste can be transferred to a syringefor injection into a mammalian body. Furthermore, the cements may besupplied with or in the instrumentation which is used to introduce thecement into the body. Examples of such instrumentation include, forexample, a syringe, percutaneous device, cannula, biocompatible packet,dentula, reamer, file, or other forms which will be apparent to those ofordinary skill in the art. It is further envisioned that the bonecements disclosed herein could be delivered into the body in such a formas to be converted by bodily processes into the bone cement compositionsdisclosed herein.

It is contemplated that any of the cements disclosed herein may be madeavailable to practitioners such as surgeons, veterinarians, or dentistsvia a kit containing one or more key components. A non-limiting exampleof such a kit comprises the dry and liquid components in separatecontainers, where the containers may or may not be present in a combinedconfiguration. Many other kits are possible, such as kits comprising asource of electromagnetic radiation in order to prepare aradiation-assisted bone cement as described herein, kits comprising apre-mixed putty instead of the powder and setting solution, and kitsincluding a syringe or multiple syringes for injecting a bone cementcomposition formed from the components of such kit. The kits typicallyfurther include instructions for using the components of the kit topractice the subject methods. The instructions for practicing thesubject methods are generally recorded on a suitable recording medium.For example, the instructions may be present in the kits as a packageinsert or in the labeling of the container of the kit or componentsthereof. In other embodiments, the instructions are present as anelectronic storage data file present on a suitable computer readablestorage medium, such as a CD-ROM or diskette. In other embodiments, theactual instructions are not present in the kit, but means for obtainingthe instructions from a remote source, such as via the internet, areprovided. An example of this embodiment is a kit that includes a webaddress where the instructions can be viewed and/or from which theinstructions can be downloaded. As with the instructions, this means forobtaining the instructions is recorded on a suitable substrate.

Alternatively, the components to form a bone cement composition asdescribed herein may be present as a packaged element. The cements aregenerally provided or employed in a sterilized condition. Sterilizationmay be accomplished by several methods such as radiation sterilization(e.g., gamma-ray radiation), dry heat sterilization, or chemical coldsterilization.

The bone cements disclosed herein may be further used for drug delivery.A drug can be dissolved in a bone cement paste, or a bone cementcomposition (before or after it sets) can be soaked in a solutioncomprising a drug, before the composition is injected or placed into oronto an anatomical location. The drug can then be released into thesubject from the cement matrix. Embodiments resulting in sustainedrelease of drugs are also envisioned, for instance by coating the cementmatrix with polymers including PLA/PGA, polyacrylic acid, hydroxylmethylcellulose, and/or chitosan.

Example 1

A 15 mL setting solution was prepared by mixing 0.0032 g citric acidmonohydrate, 6.0 g NaHCO₃, 3.0 mL H₂O, and 12 mL H₃PO₄ (86.2%). The pHof the setting solution was 0.25±0.01, and was stable over a shelf lifeof 6 months. The setting solution was stored in a tightly-capped glassbottle.

The powder component of the cement comprised only Ca(OH)₂ (>95%, FisherScientific). 1.235 g Ca(OH)₂ was mixed with 0.8 mL H₂O in an agatemortar using an agate pestle. 1.5 mL of the setting solution was thenadded to the mixture, and an agate pestle was used to manually mix thepowder and liquid, giving a paste-like substance at the end of 2.5 to 3minutes. In a 37° C. environment, the paste hardened after 33 minutes,showing a strength of about 10 MPa.

Surface modification of chitosan for better bonding to monetite cementwas achieved by mixing 3 g of 98% orthophosphoric acid, 15 g urea, 15 mLN,N-dimethyl formamide, and 1 g of chitosan microparticles ornanoparticles in a flask. The mixture was heated to 120° C. withmagnetic stirring at 300 rpm for 1 hour. The mixture was poured intowater and filtered to collect surface-phosphorylated chitosan particles.

Chitosan-incorporated monetite cement was prepared by adding thesurface-phosphorylated chitosan particles to the setting solution withmagnetic stirring at 300 rpm for 4 hours. When the chitosan particleswere uniformly dispersed in the setting solution, the new settingsolution was ready for further reaction. 1.235 g Ca(OH)₂ was mixed with0.8 mL H₂O in an agate mortar using an agate pestle. 1.5 mL of the newsetting solution was then added to the mixture and the agate pestle wasused to manually mix the powder and liquid to form a paste. Afterhardening, the monetite cement showed strength above 20 MPa.

FIG. 1 shows the formation of phases from the setting solution (with 5%added chitosan as a representative composition) at the intermediate timepoints 10 minutes, 20 minutes, 40 minutes, and 12 hours, by stopping thereactions in ethanol. All the peaks (other than Ca(OH)₂) are assigned tomonetite (DCPA). FIG. 2 shows flow patterns of the injected cement pastewith 0, 3, 5, and 10% by weight chitosan. The results show that with theaddition of 10% chitosan, the cement paste does not flow continuously inspite of using just one solid ingredient. A 10% composition will notfill a bone defect cavity uniformly, resulting in non-uniform bonegrowth. FIG. 3 is an SEM micrograph of the cement with differentchitosan content. FIG. 4 is an SEM micrograph of osteoblast cells oncement samples after 72 hours of seeding. The biocompatibility of thesurface is shown by cell spreading, with cement particles visibleunderneath the osteoblasts. This proves the biocompatibility of thecement. FIG. 5 displays the compressive strength improvement of thecement after the addition of surface phosphorylated chitosan.

Example 2

Cement pastes were prepared by manually mixing Ca(OH)₂ with settingsolution and DI water in an agate mortar by using an agate pestle. Forpreparing 15 mL of the setting solution, 0.0032 g of citric acidmonohydrate (CAM, C₆H₈O₇.H₂O, 100%), 6 g of sodium bicarbonate(NaHCO₃, >99.7%), 1.95 mL of DI water for diluting the setting solution,and 13.05 mL of phosphoric acid (H₃PO₄, 85%) solution as a source ofphosphate, were mixed respectively. Initially, 0.6175 g of Ca(OH)₂ wasmixed at least two minutes with 0.8 mL of DI water to form a paste withCa(OH)₂ uniformly dispersed in the water. Finally, 0.75 mL of settingsolution was added to the materials.

The mixed paste was transferred to a household microwave with 1300 Wenergy input and baked for 5 minutes at maximum power. The resulted masswas crushed into fine powders using a pestle. 1 g of the monetitepowders was then mixed with 0.5-0.8 mL water or nanosilica sol. In bothcases, the formed paste could be shaped and injected, and was capable ofself-setting at 45° F., 73° F., and 98.6° F. environments. The maximumcompressive strength of the monetite-silicate cement reached 65 MPa,ideal for weight-bearing applications. FIG. 8 shows XRD patterns ofmonetite (DCPA) cements formed with and without using thisradiation-assisted technique. FIG. 9 shows a scanning electronmicroscope (SEM) micrograph of preosteoblast cells on themonetite-silica cement samples after 72 hours of seeding. FIG. 12 showsthe difference in heat generated during mixing reactants with water,with and without the microwave-assisted technique.

Example 3

Cement pastes were prepared by manually mixing Mg(OH)₂ with settingsolution and DI water in an agate mortar by using an agate pestle. Forpreparing 15 mL of the setting solution, 0.0032 g of citric acidmonohydrate (CAM, C₆H₈O₇.H₂O, 100%), 6 g of sodium bicarbonate(NaHCO₃, >99.7%), 1.95 mL of DI water for diluting the setting solution,and 13.05 mL of phosphoric acid (H₃PO₄, 85%) solution as a source ofphosphate, were mixed respectively. 2.47 g of Mg(OH)₂ was added to amixture of 2 mL of DI water and 3 mL of setting solution to form apaste.

The mixed paste was transferred to a household microwave with 1300 Wenergy input and baked for 5 minutes at maximum power. The resulted masswas crushed into fine powders using a pestle. 2 g of the MPC powderswere then mixed with 0.5-0.8 mL water or nanosilica sol. In both cases,the formed paste could be shaped and injected, and was capable ofself-setting at 45° F., 73° F., and 98.6° F. environments.

Example 4

A cement paste was prepared by adding 1.235 g Mg(OH)₂ to a mixture of0.5 mL DI water and 1.5 mL setting solution. The paste hardened intodisk samples. The same paste, freshly prepared, was treated withmicrowaves for 10 minutes to prepare powders. The 1 g of synthesizedpowders was mixed with 0.4 mL DI water to form a paste that set into ahardened mass. FIG. 13 compares the XRD patterns of Mg—P precursorsformed after microwave treatment, Mg—P cement formed by direct mixingwith Mg(OH)₂ and H₃PO₄, and hardened Mg—P cement after microwavetreatment. FIG. 14 shows SEM images of the precursors, cement formedfrom direct mixing, and cement formed after microwave treatment. Theformed Mg—P is newberyite (MgHPO₄.3H₂O).

After 7 days incubation in simulated body fluid, the Mg—P cement wasconverted into apatite with plate-like crystals and Mg₂₊, Ca₂₊, Na⁺, andPO₄ ³⁻ ions. FIG. 15 shows an SEM image depicting this. FIG. 16 shows anXRD pattern of the Mg—P cement after 7 days SBF incubation, indicatingpartial newberyite (MgHPO₄.3H₂O) was converted into bobierrite(Mg₃(PO₄)₂. 8H₂O).

Example 5

A strontium-containing cement was prepared using a setting solution ofDI water. The reactants were Mg(OH)₂ and H₃PO₄ crystals. In theprecursors' production, 3 g Mg(OH)₂ and 3.36 g H₃PO₄ were mixed with 3mL water. After 1 minute of mixing, the formed paste was sent to amicrowave oven for 5 minutes of maximum power heating treatment. Theformed brittle material was crushed into fine powders. The powders weremixed with water containing SrCl₂ (0.01 g SrCl₂ to 1 mL water) at aweight/volume ratio of 3 g/mL to form a paste, which set after 5minutes. Since such a small amount of SrCl₂ was added, no change to theXRD pattern of the resulting cement can be seen.

While various examples herein describe cements having Ca—P phases as thepredominant component, other alkaline earths such as Sr can be added tosynthesize doped Ca—P phases. In embodiments with Sr-doped Ca—P or Mg—Pphases, the resulting cement has radio opacity and promotes cell growth.This will be readily apparent to practitioners skilled in the art.

The term “cement” herein is used interchangeably with paste, slurry,putty, cement formulation, and cement composition. The term “between” isused in connection with a range that includes the endpoints unless thecontext suggests otherwise. The term “shelf-life” herein means that thecalcium phosphate mineral(s) will set when mixed with a solvent to forma cement after the powder has been stored in a sealed container for apredetermined period of time, most preferably for at least 6 months ormore. The term “setting solution” herein means the solution leading toredox reactions. The term “injectable” as used in accordance with thepresent disclosure refers to when the calcium phosphate minerals aremixed with a solvent to form a cement paste and the paste is transferredto a syringe for injection into a mammalian body. The term “setting”means the hardening at room or body temperature of the paste formed bymixing a powder component and a setting solution as described herein.

Certain embodiments of the bone cement composition disclosed herein aredefined in the examples herein. It should be understood that theseexamples, while indicating particular embodiments of the invention, aregiven by way of illustration only. From the above discussion and theseexamples, one skilled in the art can ascertain the essentialcharacteristics of this disclosure, and without departing from thespirit and scope thereof, can make various changes and modifications toadapt the compositions and methods described herein to various usagesand conditions. Various changes may be made and equivalents may besubstituted for elements thereof without departing from the essentialscope of the disclosure. In addition, many modifications may be made toadapt a particular situation or material to the teachings of thedisclosure without departing from the essential scope thereof.

What is claimed is:
 1. A method of delivering a drug to a subject inneed thereof, the method comprising: preparing a bone cement compositionfrom a powder component comprising a basic source of calcium, magnesium,or strontium, and a setting solution comprising H₃PO₄, wherein the bonecement composition is a paste that sets into a hardened mass; dissolvinga drug in the bone cement composition before the paste sets; placing orinjecting the paste onto or into an anatomical location of a subject inneed of the drug; and allowing the bone cement paste to set into ahardened mass to deliver the drug to the subject in need thereof.
 2. Themethod of claim 1, wherein the bone cement composition further comprisessilica.
 3. The method of claim 1, wherein the bone cement compositionfurther comprises a biopolymer.
 4. The method of claim 1, wherein thebone cement composition further comprises one or more additives.
 5. Themethod of claim 1, wherein the bone cement composition is coated with apolymer for sustained release of the drug.
 6. The method of claim 5,wherein the polymer is selected from the group consisting of PLA/PGA,polyacrylic acid, hydroxyl methylcellulose, chitosan, and a combinationthereof.
 7. The method of claim 1, wherein the powder componentcomprises Ca(OH)₂, Mg(OH)₂, or Sr(OH)₂.
 8. A method of delivering a drugto a subject in need thereof, the method comprising: preparing a bonecement composition by irradiating a cement paste to form dry powders,and mixing the dry powders with a setting solution to form aradiation-assisted bone cement paste that sets into a hardened mass;dissolving a drug in the radiation-assisted bone cement paste before thepaste sets; placing or injecting the paste onto or into an anatomicallocation of a subject in need of the drug; and allowing theradiation-assisted bone cement paste to set into a hardened mass todeliver the drug to the subject in need thereof.
 9. The method of claim8, wherein the radiation-assisted bone cement paste comprises silica.10. The method of claim 8, wherein the radiation-assisted bone cementpaste is coated with a polymer for sustained release of the drug. 11.The method of claim 10, wherein the polymer is selected from the groupconsisting of PLA/PGA, polyacrylic acid, hydroxyl methylcellulose,chitosan, and a combination thereof.
 12. The method of claim 8, whereinthe radiation-assisted bone cement paste comprises one or moreadditives.
 13. The method of claim 8, wherein the radiation-assistedbone cement paste comprises a biopolymer.
 14. A method of delivering adrug to a subject in need thereof, the method comprising: allowing abone cement composition to set into a hardened mass, wherein the bonecement composition comprises silica; soaking the hardened mass in asolution comprising a drug; and placing the hardened mass onto or intoan anatomical location of a subject in need of the drug to deliver thedrug to the subject in need thereof.
 15. The method of claim 14, whereinthe bone cement composition comprises monetite.
 16. The method of claim14, wherein the bone cement composition comprises a biopolymer.
 17. Themethod of claim 14, wherein the bone cement composition is coated with apolymer for sustained release of the drug.
 18. The method of claim 17,wherein the polymer is selected from the group consisting of PLA/PGA,polyacrylic acid, hydroxyl methylcellulose, chitosan, and a combinationthereof.
 19. The method of claim 14, wherein the bone cement compositionis prepared by irradiating a bone cement paste to form dry powders, andthen mixing the dry powders with a setting solution to form aradiation-assisted bone cement paste that sets into a hardened mass. 20.The method of claim 19, further comprising crushing the dry powders.